The mechanism of cataract formation caused by feeding amphiphilic drugs (triparanol, chloroquine, chlorphentermine and iprindole) will be elucidated. We postulate that these compounds alter fiber cell lipid metabolism such that phosphatidylserine is lost and sphingomyelin accumulates. These lipid alterations lead to inhibition of Na+,K+=ATPase and altered lens membrane permeability resulting in the collapse of osmotic regulation, cation uptake adloss of transparency. Lenses and lens subregions from rats fed amphiphilic drugs will be assayed for Na+, K+, Ca2+, and Mg2+ content, Na+, K+-ATPase activity and cation permeability during precataractous, cataractpis and clearing periods. The phospholipid composition will be determined over the same time course and the results correlated to changes in Na+,K+-ATPase activity and cation permeability. Na ,K+-ATPase from lens will be isolated and the mechanism of its inactivation determined. The lipid requirements of the enzyme will be elucidated. The kinetics and partial reactions of normal and partially deactivated enzyme will be studied. The role of alterations in membrane fluidity and loss of essential sulfhydryl groups in enzyme inactivation by drug feeding will be evaluated. Attempts will be made to reactivate the enzyme from cataractous lens after the cause(s) of inactivation have been identified. The metabolic basis for drug-induced lipid composition alterations will be determined by pulse-chase radiolabeling studies utilizing cultured lenses. Alterations in cation transport, membrane permeability properties nd phospholipid metabolism will be correlated tem,porally to changes in the ultrastructure of lens membranes.